Role of PRMT7 in Genomic Imprinting

PRMT7 在基因组印记中的作用

基本信息

批准号：
10714206
负责人：
Taiping Chen
金额：
$ 34.83万
依托单位：
UNIVERSITY OF TX MD ANDERSON CAN CTR
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-08-17 至 2027-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10714206
关键词：
Ablation Adult Alleles Arginine Classification DNA Methylation DNA Modification Methylases DNMT3a Development Disease Embryonic Development Enzymes Epigenetic Process Exhibits Female Fertilization Gametogenesis Gene Expression Gene Order Genes Genetic study Genome Genomic DNA Genomic Imprinting Genomic Segment Germ Cells Germ Lines H19 gene Health Hydatidiform Mole Impairment Infertility Inherited Knowledge Laboratories Maintenance Malignant Neoplasms Mediating Methylation Mission Molecular Mus N-terminal Occupations Pathogenesis Pattern Play Public Health Regulation Repression Research Role Signal Transduction Specificity Spermatocytes Testing Tissues United States National Institutes of Health Work arginine methyltransferase embryonic stem cell experimental study genome-wide imprint improved innovation insight male mutant novel offspring paternal imprint public health relevance sexual dimorphism sperm cell

Ablation Adult Alleles Arginine Classification DNA Methylation DNA Modification Methylases DNMT3a Development Disease Embryonic Development Enzymes Epigenetic Process Exhibits Female Fertilization Gametogenesis Gene Expression Gene Order Genes Genetic study Genome Genomic DNA Genomic Imprinting Genomic Segment Germ Cells Germ Lines H19 gene Health Hydatidiform Mole Impairment Infertility Inherited Knowledge Laboratories Maintenance Malignant Neoplasms Mediating Methylation Mission Molecular Mus N-terminal Occupations Pathogenesis Pattern Play Public Health Regulation Repression Research Role Signal Transduction Specificity Spermatocytes Testing Tissues United States National Institutes of Health Work arginine methyltransferase embryonic stem cell experimental study genome-wide imprint improved innovation insight male mutant novel offspring paternal imprint public health relevance sexual dimorphism sperm cell

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项目摘要

PROJECT SUMMARY/ABSTRACT Genomic imprinting is an epigenetic gene-marking phenomenon that causes a subset of mammalian genes (i.e. imprinted genes) to be expressed from only one of the two parental copies. The majority of imprinted genes are arranged in chromosomal clusters. Each cluster has an imprinting control region (ICR) with one or more differentially methylated regions (DMRs) - regions marked by DNA methylation on only one allele - which act as the epigenetic signal that controls monoallelic expression. Imprinted DMRs are classified as germline (primary) DMRs (gDMRs) and somatic (secondary) DMRs (sDMRs). gDMRs are established during gametogenesis, resulting from differential de novo methylation of male and female germ cells. sDMRs represents allele-specific methylation acquired during embryonic development. Genetic studies have demonstrated that the de novo DNA methyltransferase DNMT3A is responsible for the establishment of methylation imprints at gDMRs during germ cell development and that the maintenance enzyme DNMT1 is responsible for maintaining methylation imprints during embryonic development and in adult tissues. Despite these advances, fundamental questions remain to be answered, e.g. How sexually dimorphic patterns of DNA methylation in gametes are regulated? And how gDNAs control sDMRs? Preliminary studies in the applicant’s laboratory showed that conditional ablation of the arginine methyltransferase PRMT7 in male germ cells results in incomplete methylation of the gDMR at the H19-Igf2 imprinted locus in sperm. As a result, the progeny show biallelic repression of Igf2 and allelic switch in H19 and Gtl2 expression (Gtl2 is also a paternally imprinted gene). The applicant’s laboratory also showed that PRMT7 catalyzes monomethylation of DNMT3A at a conserved arginine residue in the N-terminal region that is important for functional specificity of DNMT3A. The applicant hypothesizes that PRMT7, through methylating DNMT3A, regulates DNMT3A-mediated de novo methylation, including the establishment of paternal imprints, during male germ cell development and that, in the absence of PRMT7, impaired DNA methylation on the paternal alleles causes secondary trans-effect changes on the maternal alleles after fertilization, resulting in allelic switch in the expression of some paternally imprinted genes. To test the hypothesis, the applicant proposes two specific aims: 1) Determine the role of PRMT7 in de novo DNA methylation during male germ cell development; and 2) Elucidate the mechanism underlying allelic switch of paternally imprinted genes in the offspring of PRMT7-deficient male mice. In the applicant’s opinion, the proposed research is innovative for its conceptual novelty. The project is significant, because results from the proposed studies are expected to provide novel insights into the regulation of de novo DNA methylation in the male germline and the crosstalk between the paternal and maternal alleles to control monoallelic expression of imprinted genes.

项目摘要/摘要基因组印记是一种表观遗传基因标记现象，会导致哺乳动物基因的子集（即印迹基因）仅从两个父母副本中的一个来表达。大多数印迹基因是在染色体簇中排列。每个集群都有一个或多个烙印控制区（ICR）差异甲基化区域（DMR） - 仅在一个等位基因上以DNA甲基化为标志的区域 - 作为控制单相表达的表观遗传信号。印迹DMR被归类为种系（主要）DMR（GDMR）和体细胞（次级）DMR（SDMR）。 GDMR是在配子发生是由雄性和女生殖细胞的从头甲基化差异引起的。 SDMR代表等位基因特异性甲基化在胚胎发育过程中获得。遗传研究表明从头DNA甲基转移酶DNMT3A负责在GDMRS上建立甲基化烙印在生殖细胞发育过程中，维护酶DNMT1负责维持胚胎发育和成年组织中的甲基化烙印。尽管有这些进步，但基本问题仍有待回答，例如游戏中DNA甲基化的性二态模式是如何的受监管？ GDNA如何控制SDMR？申请人实验室的初步研究表明在男性生殖细胞中精氨酸甲基转移酶PRMT7的条件消融导致不完整 H19-IGF2印迹基因座的GDMR的甲基化。结果，后代显示双质体 H19和GTL2表达中IGF2和等位基因开关的抑制（GTL2也是亲子印象基因）。这申请人的实验室还表明，PRMT7催化DNMT3A的单甲基化在组成的精氨酸居住在N末端区域，对于DNMT3A的功能特异性很重要。申请人假设PRMT7通过甲基化DNMT3A调节DNMT3A介导的从头甲基化，包括建立父亲的烙印，在男性生殖细胞发育过程中，并且在没有的情况下 PRMT7，父亲等位基因上的DNA甲基化受损会导致次要反式变化受精后的母体等位基因，导致某些父子烙印基因表达的等位基因转换。为了检验假设，适用的提案有两个具体的目的：1）确定prmt7在从头开始的作用男性生殖细胞发育过程中的DNA甲基化； 2）阐明等位基因开关的机制 PRMT7缺乏雄性小鼠的后代的父亲印迹基因的含量。申请人认为拟议的研究以其概念新颖性而具有创新性。该项目很重要，因为预计拟议的研究将提供对从头DNA甲基化调节中的新见解。男性种系以及父亲和母亲等位基因之间的串扰，以控制单相表达印迹基因。